The present invention relates to a novel process of preparing tolterodine and analogues thereof, as well as to novel intermediates prepared in the process.
Tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropanamine, is useful for treating urinary incontinence. The major, active metabolite of tolterodine, i.e. (R)-N,N-diisopropyl-3-(2-hydroxy-5-hydroxymethylphenyl)-3-phenylpropanamine, contributes significantly to the therapeutic effect of tolterodine. Tolterodine and analogues thereof, including the corresponding (S)-enantiomer, as well as processes for the preparation thereof are disclosed in U.S. Pat. No. 5,382,600. The active metabolite and analogues are disclosed in U.S. Pat. No. 5,559,269. The (S)-enantiomer and its use in the treatment of urinary and gastrointestinal disorders is further described in WO 98/03067.
One of the processes described in U.S. Pat. No. 5,382,600 comprises the steps of preparing the lactone 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-one, reductively ring-opening the lactone to prepare the corresponding alcohol, reacting the alcohol with isopropylamine, and resolving the racemate formed to isolate tolterodine.
U.S. Pat. No. 5,922,914 discloses a modified process for preparing tolterodine by reducing the above-mentioned lactone to the corresponding alcohol, 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol, reductively aminating the alcohol, and resolving the racemate formed to isolate tolterodine.
While the above prior art methods thus produce a racemate which has to be resolved to obtain the desired tolterodine enantiomer, Andersson, Pher G. et al., J. Org. Chem. 1998, 63, 8067-8070 discloses an enantioselective synthesis of tolterodine which obviates the need of the enantiomer separation step. This method comprises a copper bromide catalyzed asymmetric addition of 2-methoxy-5-methylphenylmagnesium bromide to a 3-phenyl-prop-2-enoyl-oxazolidinone to produce the (5S)-phenyl-3R)-2-benzyloxy-5-methylphenyl)-3-phenylpropanoyl-2-oxazolidinone, hydrolyzation of the oxazolidinone to the corresponding propanoic acid, reaction with diisopropylamine to form the amide, and reduction of the amide to tolterodine.
The present invention provides an alternate enantioselective synthesis of tolterodine which is more convenient to perform than the prior art method outlined above and which gives a final product of high enantiomeric purity. A key step of the present method is the preparation of the above-mentioned lactone, 3,4-dihdyro-6-methyl-4-phenyl-2H-benzopyran-2-one (also referred to as 6-methyl-4-phenyl-chroman-2-one), in an enantiomerically enriched form by enantioselective reactions.
Thus, in a first aspect the present invention provides a process for the enantioselective preparation of a compound of the general formula (Ia) or (Ib): 
xe2x80x83wherein R1, R2 and R3 independently of each other are hydrogen, methyl, methoxy, hydroxy, hydroxymethyl, carbamoyl, sulphamoyl or halogen, and R4 and R5 independently of each other are C1-6-alkyl, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II): 
xe2x80x83wherein R1, R2 and R3 are as defined above, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb): 
xe2x80x83wherein R1, R2 and R3 are as defined above, or a salt thereof;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb): 
xe2x80x83wherein R1, R2 and R3 are as defined above, or a salt thereof;
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form a corresponding enantiomerically enriched compound of the general formula (Va) or (Vb): 
xe2x80x83wherein R1, R2 and R3 are as defined above or a salt thereof;
d) converting the compound of formula (Va) or (Vb) to form the corresponding enantiometrically enriched compound of formula (Ia) or (Ib), or a salt thereof; and
e) optionally converting a compound of formula (Ia) or (Ib) in base form to a salt thereof, or converting a salt form to the free base.
In one embodiment of the first aspect of the invention, step d) comprises:
d1) reacting the compound of formula (Va) or (Vb) with an amine of the general formula (VI): 
xe2x80x83wherein R4 and R5 are as defined above, to form a corresponding enantiomerically enriched compound of the general formula (VIIa) or (VIIb): 
xe2x80x83wherein R1, R2, R3, R4 and R5 are as defined above; and
d2) reducing the carbonyl function in the compound of formula (VIIa) or (VIIb) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
Optionally, steps d1) and d2) are performed simultaneously in a single step.
In an alternative embodiment, step d) comprises:
d1xe2x80x2) reducing the compound of formula (Va) or (Vb) to form a corresponding enantiomerically enriched hydroxy compound of the general formula (VIIIa) or (VIIIb): 
xe2x80x83wherein R1, R2 and R3 are as defined in claim 1; and
d2xe2x80x2) reductively aminating the hydroxy compound of formula (VIIIa) or (VIIIb) with the amine of formula (VI) to form the corresponding enantiomerically enriched compound of formula (Ia) or (Ib).
In second aspect, the present invention provides a process for the enantioselective preparation of a compound of the general formula (Va) or (Vb): 
xe2x80x83wherein R1, R2 and R3 are as defined above, or a salt thereof, which process comprises the steps of:
a) enantioselectively reducing the carbonyl function in a compound of formula (II): 
xe2x80x83wherein R1, R2 and R3 are as defined above, or a salt thereof, to form an enantiomerically enriched compound of formula (IIIa) or (IIIb): 
xe2x80x83wherein R1, R2 are R3 are as defined above, or a salt thereof;
b) subjecting the compound of formula (IIIa) or (IIIb) to a sigmatropic rearrangement to form a corresponding enantiomerically enriched compound of formula (IVa) or (IVb): 
xe2x80x83wherein R1, R2 and R3 are as defined above, or a salt thereof; and
c) subjecting the compound of formula (IVa) or (IVb) to a Baeyer-Villiger oxidation to form the corresponding enantiomerically enriched compound of the general formula (Va) or (Vb), or salt thereof.
The compound of formula (II) may be prepared by subjecting a compound of the general formula (IX): 
xe2x80x83wherein R1, R2, and R3 are as defined in claim 1, and Hal is halogen (preferably bromine), or a salt thereof, to a reductive ring closure reaction.
The compound of formula (IX) may be prepared by reacting a compound of the general formula (X): 
xe2x80x83wherein R1 and Hal are as defined above, with a compound of the general formula (XI): 
xe2x80x83wherein R2 and R3 are as defined above.
Preferably, compounds of formula Ia or Ib are prepared in which R1 is methyl or hydroxymethyl in 5-position, R2 and R3 are hydrogen, and R4 and R5 are both isopropyl.
In a third aspect, the present invention provides novel compounds of the above of the formulae (II), (IIIa), (IIIb), (IVa), (IVb), (Va), (Vb), and (IX) as defined above and wherein R1 is methyl or hydroxymethyl in 5-position, or for (Va) and (Vb), in 6-position, and R2 and R3 are hydrogen and compounds of the formulae (IX) wherein R1 is methyl or hydroxymethyl in 5-position or 4-position, R2 and R3 are hydrogen and halogen is Br, I or F.
A basic concept behind the present invention is the enantioselective reduction of the compound of formula (II) to a compound of formula (IIIa) or (IIIb) in enantiomerically enriched form, which is then rearranged to form the lactone (Va) or (Vb). The respective lactone enantiomers may then be reacted further to tolterodine by methods known per se in the art, e.g. as described in the above-mentioned U.S. Pat. No. 5,382,600 and U.S. Pat. No. 5,922,914.
The enantioselective reduction of the compound (II) to a compound of formula (IIIa) or (IIIb) may be performed in an organic solvent with a variety of reducing agents and reaction conditions as are known per se in the art for enantioselective reduction of carbonyl groups. Such methods are described in, for example, Houben-Weyl, Stereoselective Synthesis, Ed: Gxc3xcnter Helmchen et al., Vol. 7, Chapter 2.3, Thime, Stuttgart-New York 1996. Preferably, the reaction is carried out at from about 0xc2x0 C. to about room temperature. An exemplary method includes the use of a chiral catalyst, such as (R)- or (S)-MeCBS (3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[1,2-c][1.3.2]oxazaborole) which is commercially available, a borane complex and a base. The stereochemistry can be directed by using either the R or S enantiomer of the MeCBS oxazaborolidine catalyst in the asymmetric borane reduction of the compound (II). The reduction of a similar substrate is described in, for example, WO 97/17341. The enantioselectivity of asymmetric borane reductions is not very sensitive to stereoelectronic effects.
The sigmatropic 1,3-rearrangement (hydride shift) of the compound (IIIa) or (IIIb) to a compound of formula (IVa) or (IVb) may be carried out by treatment with a base, such as triethylamine, and a palladium catalyst, such as Pd(dppe)Cl2 ([1,2-bis(diphenylphosphino)ethane]palladium (ii) chloride) in an organic solvent (see e.g. the above WO 97/17341). Alternatively, the rearrangement reaction may be carried out by treatment with DABCO (1,4-diazabicyclo[2.2.2]octane) and a base, such as triethylamine, in an organic solvent (see Example 1 below). The indanone (IVa) or (IVb) obtained is generally a highly crystalline solid which makes it possible to raise the enantiomeric purity, if desired, by recrystallization from a suitable solvent (for example, an enantiomeric excess (as defined below) of 99% or more may be obtained).
The Baeyer-Villiger oxidation of compounds (IVa) and (IVb) may be performed by a variety of oxidizing agents as is well known in the art, e.g. hydrogen peroxide or a peroxy acid, such as 3-chloro-peroxybenzoic acid, preferably in the presence of an acid catalyst, such as p-tolysulphonic acid (TsOH). The reaction is preferably carried out in an organic solvent and at e.g. from about 0xc2x0 C. to about room temperature.
Enantiomeric purity, or enantiomeric enrichment, is usually expressed as xe2x80x9cenantiomeric excessxe2x80x9d, below abbreviated as xe2x80x9ceexe2x80x9d, and defined as (Rxe2x88x92S)/(R+S), where R and S are the amounts of the R- and S-enantiomers, respectively. For the purposes of the present invention, the enantiomeric purity in the enantioselective process steps is usually at least about 50%, preferably at least about 85%.
Since tolterodine is an amine, it may form salts with both organic and inorganic acids. The pharmaceutically acceptable salts may, depending on the pharmaceutical formulation, be preferred over the corresponding free amines since they produce compounds which are more water soluble and more crystalline. Exemplary pharmaceutically acceptable salts include salts with acids such as methane sulphonic, hydrochloric, hydrobromic, sulphuric, phosphoric, nitric, benzoic, citric, tartaric, fumaric, and maleic acids.
The invention will now be illustrated further by the following non-limiting Example.
In the Example:
TLC refers to thin-layer chromatography.
MeCBS refers to 3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo-[1,2-c][1.3.2]oxazaborole.
DABCO refers to 1,4-diazabicyclo[2.2.2]octane.
ChiralCel OD-H (trademark) refers to a chiral stationary phase for liquid chromatography consisting of cellulose tris(3,5-dimethylphenyl carbamate) on a silica gel substrate (Daicel Chemical Industries, Ltd.).
mCPBA refers to 3-chloroperoxybenzoic acid.
xe2x80x9ceexe2x80x9d refers to enantiomeric excess as defined above.